17alpha - ethynyl - 8alpha - h - delta**5(10) - estrene - 17beta - ol-3-one,process of preparation,therapeutic administration and intermediates



United States Patent US. Cl. 424243 3 Claims ABSTRACT OF THE DISCLOSUREThis invention relates to 17a-ethynyl-8e-H'A estrene-l7p-ol-3-one in itsracemic and optically active forms. This compound possesses ahypophysial inhibitory activity, an anti-fertilizing action, ananti-nidatory effect as well as an anti-ovulatory effect.

The present invention relates to new derivatives of the estrane seriesas well as to the process for the preparation of these compounds. Inparticular, the invention relates to l7a-ethynyl8a-H-A-estrene-l7fl-ol-3-one in its racemic and optically active forms.

The compounds of the invention present useful pharmacologicalproperties. Particularly they possess a hypophysial inhibitory activitycurbing the F.S.H. secretion (folliculo-stimulating hormone which isvery distinctly superior to that of 17aethynyl-A -estrene-l7fi-ol-3-one(norethynodrel), an isomer in natural form.

Furthermore,the compounds possess an antifertilizing action byinterfering in the mechanism of reproduction. At the same time,17a-ethynyl-8a-H-A -estrene-l'Ifl-ol 3-one possesses a very pronouncedaction on the implantation of ova (anti-nidatory effect) as well as ananti-ovulatory action. These elfects are always superior to thoseobtained with norethynodrel.

It is surprising to find that l7aethynyl-8a-H-A estrene-l7fi-ol-3-one ismore active than the compound in the natural form (8fl-H isomer). Infact, the contrary has been established for the known 8-iso compounds,such as, for example, S-iso-testosterone, 8-iso-estrone,8-iso-l9-nortestosterone or S-iso-progesterone.

Thus, it has been proven that the isomerization of the 8-centerdiminishes by more than one-half the virilizing effects of testosterone.In the same way, the androgenic effect of 8-iso-l9-nor-testosterone ismuch weaker than that of its isomer in the natural series, and theanabolic effect disappears almost entirely.

The increase in the hypophysial inhibitory activity curbing the F.S.H.secretion and the increase in antifertilizing action with regard to thecompound of normal structure, norethynodrel (notwithstanding theisomerization of S-center), consequently, constitute an unexpected andnonevident phenomenon.

An object of this invention is the obtention of a compound selected fromthe group consisting of the racemic and optically active forms ofl7aethynyl-8a-H-A estrene-l7fi-ol-3-0ne.

Another object of this invention is the development of a method ofcurbing recessive hypophysial activity in warm-blooded animals whichcomprises administering to said warm-blooded animals from about 0.04mg./kg. to about 6.0 mg./kg. per day, based on the body weight of saidwarm-blooded animals, of l7a-ethynyl-8a-H-A estrene-17fi-ol-3-one.

A further object of this invention is the development of a method ofsuppressing ovulation in warm-blooded 'ice animals which comprisesadministering to said warmblooded animals from about 0.04 mg./kg. toabout 6.0 mgJkg. per day, based on the body weight of said warmbloodedanimals, of 17a-ethynyl-8a-H-A -estrene-176- ol-3-one.

A yet further object of this invention is the development of a method ofsuppressing fertilization of the ova in warm-blooded animals whichcomprises administering to said warm-blooded animals from about 0.04mg./ kg. to about 10.0 mg./kg. per day, based on the body weight of saidwarm-blooded animals, of 17a-ethyny1-8a-H-A estrene-l7fl-ol-3-one.

A still further object of this invention is the development of a processfor the production of a compound selected from the group consisting ofthe racemic and optically active forms of 17a-ethynyl-8u-A-estrenel7fl-ol-3-one, which comprises the steps of (a) subjecting8a-H-A -estrene-l7fl-ol-3-one to the action of a ketalizing agent underketalizing conditions, (b) reacting the resulting 3-ketal-8a-H-A-estrene-l7B-ol with an oxidizing agent effecting oxidization of thehydroxyl group, (c) ethynylating the resulting 3-ketal-8a-H-A-estrenel7-one by means of an ethynylating agent, ((1) hydrolyzing theresulting 3-ketal-l7a-ethynyl-8a-H-A -estrene- -ol by the action of anacid and (e) recovering said 8a-H-l7a-ethynyl-A -estrene-l7p-ol-3-one.

These and other objects of the invention will become more apparent asthe description thereof proceeds.

The process for the preparation of racemic and optically activel7a-ethynyl-8a-I-l-A -estrene-l7fi-ol-3-one, a further object of theinvention, is characterized in that 811- H-A -estrene-l7fi-ol-3-one issubjected to the action of a ketalizing agent, and the formed3-ketal-8a-I-I-A estrene-l7B-ol is reacted with an oxidizing agent, thusobtaining the corresponding l7-ketonic compound, which by the action ofan ethynylating reactant, followed by acid hydrolysis, supplies thedesired l7a-ethynyl-8a-H-A estrene-l7fl-0l-3-One.

Advantageously, the process of the invention is conducted as follows:

(1) The 3-ketone of 8a-H-A -estrene-l7fl-ol-3-one may be protected inthe form of either an ethylene ketal or a dimethyl ketal.

(2) The oxidation of the ketalized product may be effected by the actionof chromic anhydride in pyridine or by the Oppenauer method.

(3) In order to ethynylate the oxidized product, an alkali metalacetylide may be utilized, prepared by starting with an alkali metalalkanolate and acetylene, such as potassium acetylide obtained bystarting with potassium tert.-amylate. Likewise, a magnesium ethynylhalide may be used, such as the iodide, bromide or chloride whileworking in an organic solvent.

(4) The acid hydrolysis of the ethynylation product may be etiected byaction of a dilute acid such as aqueous acetic acid.

The following examples will serve for a better comprehension of theinvention, but it is to be understood, however, that they do not limitthe invention in any manner.

EXAMPLE I Preparation of l7a-ethynyl-8m-H-A -estrenel7fi-ol-3-one StepA: Preparation of 3-ethylenedioxy-8a-H-A estrene-l7B-ol.Under anatmosphere of nitrogen, 3.64 gm. of 8a-l-l-A -estrene-l7fi-ol-3-one wereintroduced into 36 cc. of anhydrous benzene. Next, 55 cc. of technicalmethyl ethyl dioxolane, containing less than 2% of ethylene-glycol, and0.11 gm. of p-toluene sulfonic acid were added, and the mixture wasagitated overnight at room temperature. Thereafter, the reaction mixturewas poured into water containing sodium bicarbonate and extracted withmethylene chloride.

The extracts obtained were washed with water, dried and evaporated todryness under vacuum. The residue was iced and then crystallized from anisopropyl ethercyclohexane mixture.

3.175 gm. of 3-ethylenedioxy-8a-H-M -estrene-17B- ol were obtained,having a melting point of 115 C. and a specific rotation [a] =0 (c.=0.5%in dioxanc).

This product occurred in the form of colorless crystals, insoluble indilute aqueous acids and alkalis, and soluble in most of the usualorganic solvents.

Analysis.C H O molecular weight=3l8.44. Calculated (percent): C, 75.43;H, 9.49. Found (percent): C, 75.3; H, 9.5.

As far as the applicants know, this compound is not described in theliterature.

The starting substance, namely, 8a-HA -estrene- 17B-ol-3-one, can beprepared according to the process described in French Pat. No.1,404,413.

Step B: Preparation of 3-ethylenedioxy-8a-H-A estrene-17-one.1.5 gm. ofchromic anhydride were introduced into 15 c. of pyridine cooled to aboutC. The solution was agitated for 15 minutes, then 1.5 gm. of3-ethylenedioxy-8a-H-A -estrene1748-01 dissolved in cc. of pyridine wereadded and the agitation was continued overnight at room temperature.

Thereafter, the reaction mixture was poured into 60 cc. of methanol,agitated for 6 hour, then 60 cc. of methylene chloride were added. Thereaction mixture was filtered and the filtrate was washed with water.After the organic phase had been dried, it was purified by passing itover magnesium silicate and finally evaporated to dryness under vacuum.

in this way, 1.34 gm. of 3-ethylenedioxy-8e-H-A estrene-l7one wasobtained, having a melting point of 148 C. and a specific rotation [a]=+6l.4 (c.=0.5% in dioxane).

The product occurred in the form of small colorless rods, insoluble indilute aqueous alkalis and acids, and soluble in most of the commonlyknown organic solvents.

AnaIysis.C H-, O molecular weight=316.42. Calculated (percent): C,75.91; H, 8.92. Found (percent): C, 75.8; H, 8.9.

As far as the applicants know, this compound is not described in theliterature.

The oxidation of 3-ethylenedioxy-8a-H-A -estrenecc. of cyclohexanone and200 cc. of anhydrous toluene.

The solution was heated to boiling point. Then within the space of 2V2hours, 1.30 gm. of aluminum isopropylate in 120 cc. of toluene wereadded thereto. The solution was heated at reflux for /2 hour longerwhile distilling 120 cc. of solvent therefrom. The solution was thencooled. Next, 4.5 gm. of potassium carbonate and 9 gm. of sodiumpotassium tartrate in 90 cc. of water were added, and the mixture thusformed was subjected to steam distillation for 2 hours. After themixture was cooled, it was extracted with ether. The extracts werewashed with water and evaporated to dryness under vacuum. The residuewas subjected to chromatography through silica gel with elution withmethylene chloride. 3-ethylenedioxy-8a-H-A -estrene-17-one was obtained,having a melting point of 148 C., identical to the product described inthe preceding step.

Step C: Preparation of 3-ethylenedioxy-17a-ethynyl- 8a-H-A-estrene-17fl-ol.Under an atmosphere of nitrogen, 6 gm. of potassium insmall pieces were introduced into 60 cc. of tert.-amyl alcohol and 60cc. of

4 anhydrous benzene, and the suspension was agitated for 1 hour at about60 C. A stream of acetylene was substituted for the atmosphere ofnitrogen, which stream was allowed to bubble through the suspension for1 /2 hour.

Next, the suspension was cooled to room temperature; then 1.22 gm. of3-ethylenedioxy-8a-H-A -estrene-l7- one dissolved in 38 cc. oftetrahydrofuran and 24 cc. of benzene were added. The solution wasagitated for 2 hours 15 minutes, while the stream of acetylene continuedto bubble through the solution. Thereafter, the reaction mixture waspoured into water. The organic phase was decanted, dried and evaporatedto dryness under vacuum.

The residue obtained was crystallized from isopropyl ether. Afterinitiation of crystallization by scratching, .125 gm. of3-ethylenedioxy-17a-ethynyl-8e-H-A estrene-17 8-ol were obtained, whichproduct was used as such for the next step in the synthesis.

As far as the applicants know, this compound is not described in theliterature.

The ethynylation of 3 ethylenedioxy 8a-H-A estrene-17-one may also beaccomplished by means of ethynyl magnesium halide. The work was carriedout in the following manner:

A stream of methyl bromide was allowed to bubble through a suspension of12.5 gm. of magnesium in 200 cc. of anhydrous ether under reflux. 270cc. of tetrahydrofuran were added to cc. of the magnesium solu tionobtained and acetylene was allowed to bubble through the solution for 3hours.

In this manner an ethynyl magnesium bromide solution was obtained, intowhich 1.26 gm. of 3-ethylcne-dioxy-8a-H-A -estrenc-17-one dissolved in40 cc. of tetra hydrofuran were introduced. The stream of acetylene wasmaintained and the solution was heated for 2 hours under reflux.Thereafter, the solution was cooled, cc. of a saturated solution ofammonium chloride were added; then the mixture was poured into water andextracted with ether.

The evaporation of the ethereal solution yielded a residue which wascrystallized from isopropyl ether to obtain 3 ethylenedioxy17a-ethynyl-8e-H-A -estrene-175- 01, which product was used withoutfurther purification for the next step of the synthesis.

Step D: Preparation of l7a-ethynyl-8m-H-A -estrenc- 17fl-ol3-one.-l.25gm. of 3-ethylenedioxy-17a-ethynyl- Sa-H-A -estrene-175-01 wereintroduced into 50 cc. of acetic acid containing 25% of water and thesolution was agitated for 5 hours at room temperature. Thereafter, thereaction mixture was poured into a mixture of water, ice and sodiumbicarbonate and agitated for one hour.

The reaction mixture was next vacuum filtered. The crystals were washedwith water until the wash waters were neutral and then dried, thusobtaining 920 mg. of crystallized product.

Starting from the motor liquors which were extracted with methylenechloride, mg. more of the same product were recovered.

After subjecting the product obtained to chromatography throughmagnesium silicate with elution with methylene chloride containing 0.5%of acetone, the eluate was crystallized from cold cyclohexane, thusobtaining 510 mg. of 17e-ethynyl-8a-H-A -estrene-17fl-ol-3-one, having amelting point of 130 C. and a specific rotation [a] =47.5 (c.=0.5% indioxane).

The product occurred in the form of colorless needles, insoluble inwater, in dilute aqueous acids and alkalis, slightly soluble in benzene,and soluble in alcohol, ether, acetone and chloroform.

A na1ysis.C H O molecular weight=298.41. Calculated (percent): C, 80.49;H, 8.78. Found (percent): C, 80.6; H, 8.8.

As far as the applicants know, this compound is n t described in theliterature.

EXAMPLE II Preparation of racemic l7aethynyl-8a-H-A -estrenel7fl-ol-3oneStep A: Preparation of racemic 3-ethylenedioxy-8a-H- A-estrene-l7fl-ol.3.64 gm. of racemic Snell-A estrene-17dol-3-one weredissolved in a solution of 0.110 gm. of p-toluene sulfonic acid, 36 cc.of benzene and 55 cc. of methyl ethyl dioxolanc. After being agitatedovernight under an atmosphere of nitrogen at a temperature of to C., thereaction mixture was poured into a sodium bicarbonate solution. Theorganic phase was extracted with methylene chloride, then the organicphases were combined, washed with water until the wash waters wereneutral, dried over potassium carbonate and evaporated to dryness, 4.800gm. of raw product were thus obtained. The product obtained was purifiedby crystallization from a mixture of isopropyl ether and cyclohexane (l:1). The solution obtained was cooled for 1 hour at 5 C. Thereafter, thecrystals were filtered and vacuum filter ed, washed with the icedisopropyl ether-cyclohexane mix ture and dried under vacuum. 3.175 gm.of product were recovered. By concentration of the mother liquors, asecond yield of 0.400 gm. was obtained. The overall yield amounted to84%. For analysis, the product was purified by recrystallization fromthe isopropyl ether-cyclohexane mixture (1:1). In this way, racemic3-ethylenedioxy-8a- I-l-M -estrene-Up-ol was obtained in the form of acolorless crystallized product, insoluble in water and slightly solublein isopropyl ether. The compound has a melting point of 126 C. to 127 C.

As far as the applicants know, this product is not described in theliterature.

The starting product, namely, racemic Snell-A estrene-l7fl-ol-3-one, wasobtained according to the process described in French Pat. No.1,404,413.

Step B: Preparation of racemic 3ethylenedioxy-8a-H- A-estrene-l7-one.-1.5 gm. of chromic anhydride were introduced into 15cc. of pyridine at a temperature of 0 to +5 C., and the solution wasagitated for 15 minutes at 5 C. to 10 C. Then a solution of 1.5 gm. ofracemic 3-ethylenedioxy-8a-l l-d -estrene-l75-ol were added to thepyridine solution while maintaining the temperature at about 0 C. Thereaction mixture was agitated overnight at room temperature. Next, 60cc. of methanol were added to the reaction mixture which was thenagitated for minutes; finally 60 cc. of methylene chloride were addedthereto. The insoluble mineral matter was filtered off. The filtrate waswashed with water and dried over potassium carbonate. The solution waspassed through a column of magnesium silicate, then evaporated todryness. 1.340 gm. of 3-ethylenedioxy-8a-H-A estrene-17-one wererecovered, which product was purified by trituration with isopropylether at reflux and icing. Thus, 1.200 gm. of pure product wererecovered. having a melting point of 142 to 143 C. On recrystallizationfrom ethanol, by heating and cooling, 0.636 gm. of racemic3-ethylenedioxy-8a-H-A -estrene-17-one were obtained in the form of acolorless crystallized product, which was insoluble in water and indilute aqueous alkalis, slightly soluble in ethyl acetate, isopropylether and alcohols, and having a melting point of 143 to 144 C.

To the best knowledge of the applicants, this product is not describedin the literature.

Analysis.C l-1 O molecular weight-=3 16.42. Calculated (percent): C,75.91; H, 8.92. Found (percent): C, 75.9; H, 8.8.

Step C: Preparation of racemic 3-ethy1enedioxy-17aethynyl-8a-H-A-estrene 17,8 ol.-Under an atmosphere of nitrogen, 145 cc. of tert=amylalcohol, 145 cc. of benzene and 14 gm. of potassium were admixed. Themixture was kept under agitation for one hour at a temperature of to C.Then a stream of acetylene was allowed to bubble through the mixture fora period of 1 /2 hours. The reaction mixture was returned to roomtemperature and a solution of 2.9 gm. of racemic 3-ethy1enedioxy-8a-H-A-estrene-l7-one in cc. of tetrahydrofuran and 58 cc. of benzene wasadded thereto. The ambient temperature was maintained, under anatmosphere of acetylene, for 2% hours. Thereafter, the excess acetylenewas eliminated by a stream of nitrogen. Next, the reaction mixture wasagitated for 15 minutes. Then 85 cc. of water were added withoutexceeding a temperature of 30 C. The organic phase was decanted, washedwith water until the wash waters were neutral, then dried over sodiumsulfate and evaporated to dryness under vacuum. Thus, 3.14 gm. of rawproduct were obtained. The raw product was triturated, at reflux, in 20cc. of isopropyl ether and kept under refrigeration overnight. 2.39 gm.of racemic 3-ethylenedioxy-17a-ethynyl-8a-H- A -estrene-l7fi-ol wererecovered, having a melting point of to 166 C.

As far as the applicants know, this product is not described in theliterature.

Step D: Preparation of racemic 17a-ethynyl-8a-H- A-estrene-17B-ol-3-one.2.39 gm. of racemic3ethylenedioxy-17a-ethynyl-8a-H-A -estrene 17p 01 were introduced into96 cc. of acetic acid containing 25% of r water. The solution wasagitated at room temperature for 5 hours. Thereafter, under continuedagitation, the reaction mixture was poured into an aqueous solution ofsodium bicarbonate and agitated for one hour. The precipitate formed wasfiltered, then vacuum filtered, washed with water until the wash waterswere neutral and finally dried under vacuum. 1.922 gm. of product werethus obtained, having a melting point of 192 C. The product was thenpurified by subjecting it to chromatography through magnesium silicateand elution first with methylene chloride, then with methylene chloridecontaining 1% of acetone. The purified product was redissolved inacetone under reflux and concentrated. On icing overnight, 2.75 gm. ofracemic l7a-ethynyl-8a-1-1-A estrene-17fl-ol-3-one were obtained, beinga total yield of 62%, having a melting point of 198 C.

The product obtained was insoluble in water, in dilute aqueous acids andalkalis, and slightly soluble in isopropyl ether and acetone.

AnaIysis.-C H O molecular weight-98.41. Calculated (percent): C, 80.49;H, 8.78. Found (percent): C, 80.2; H, 8.8.

To the best knowledge of the applicants, this product is not describedin the literature.

As it has been indicated in the preceding, l7a-ethynyl 8a-H-A-estrene-17;3-01-3-one, in its racemic and optically active forms, isendowed with interesting pharmacological properties. In particular, itpossesses a curbing action on the hypophysis. The compound may beutilized for the treatment of excessive amounts in the hypophysis of theF.S.H. factor (folliculo-gonadotropic stimulating hormone), due tocastration or menopause and, in general fashion, in all those caseswhere a curbing of the hypophysial gonadotrophines is desirable.

Furthermore, the product possesses in warm-blooded animals anantifertilizing action by intervening in the mechanism of reproduction.It has a very distinct antinidatory effect as well as an anti-ovulatoryeffect.

l7a-ethynyl-Sa-H-A -estrene-17fl ol 3 one may be utilized orally,perlingually, transcutaneously or rectally. The product can be preparedin the form of injectable solutions or suspensions, prepared in ampulesand in multiple-dose fiacons; in implants, in tablets, coated tablets,sublingual tablets and suppositories.

The useful dosology for warm-blooded animals is controlled between 0.04mg./kg. to 10.0 mg./kg. per day, or preferably between 2 and 30 mg. perday for the adult as a function of the method of administration.

The pharmaceutical forms such as injectable solutions or suspensions,implants, tablets, coated tablets, sublingual tablets and suppositoriesare prepared according to the usual processes.

7 EXAMPLE 111 Pharmacological study of l7a-ethynyl-8a-H-n-estrenel7fi-ol3-one (1) Determination of the hypophysial inhibitoryeffect: Many couples of female rats, each couple being sisters of thesame litter, aged 30 days, were united parabiotically. One of thesubject animals were castrated on the same day, and the treatment withthe medicine was started on the day after the parabiotic union for aperiod of days. The animals were sacrificed on the llth day after theparabiotic union. The genital organs were removed and weighed.

In this experiment, the castrated rats received orally a dose of 5, 10,25, S0 and 757 per day for a period of 10 days of racemicl7a-ethynyl-8a-H-A -estrene-l7 6- ol-3-one admixed with olive oilcontaining 5% benzyl alcohol.

The experiment included control animals united in parabiotic union: acastrated animal united in parabiotic union with a whole animal,receiving only the solvent.

The test was conducted in comparison with nor-ethynodrel (l7a-ethynyl-A-estrene-l7fi-ol-3-one) administered under the same conditions at dailydoses of 5, 10, and 407.

The results have been summarized in the following table.

The weight of the ovaries of the animals at the time of castration wasin the neighborhood of 20 mg. The average weight of the ovaries of thereceiver animals allows one to estimate the degree of inhibition of thehypophysial excess. The inhibition was the more complete in the sameproportion as the increase in the weights of the ovaries of the receiveranimals was the least in comparison with the weight of the ovaries ofthe animals at the time of their castration.

The dose, which diminished the rate of fertility from 80% to 100%, was0.2 mg. administered daily for 3 days for levorotatoryl7at-ethynyl-8a-H-A -estrene-l75-01-3- one (in dioxane), and 1 mg.administered daily for 3 days for norethynodrel.

The product under study was, consequently, five times more active inregard to the transportation and fixation of the fertilized ovum thannorethynodrel.

(B) Anti-ovulatory action: The anti-ovulatory activity was determinedaccording to the technique employed by 7V1ela5rgg (Annuals of the NewYork Academy of Science,

Some female rats aged about 3 months, previously treated for a period of7 days and thereafter coupled, were separated from the male animalsafter coitus had taken place (ascertained by the presence ofspermatozoids in the vaginal smears). The animals were sacrificed 8 daysafter coitus.

Lcvorotatory l7aethynyl-8a-H-A -estrene-17,8-01-3- one(in dioxane) andnorethynodrel were administered ora y.

The daily dose, which lessened the rate of fertility from 80% to 100%,was 1 mg. for a period of 7 days for levorotatory l7a-ethynyl-8e-H-A-estrene-l7fl-ol-3-one (in dioxane), and 2 mg. for a period of 7 daysfor norethynodrel.

Levorotatory l7a-ethynyl-8a-H-A -estrene-17501-3- one (in dioxane) was,therefore, twice as active as norethynodrel based on this test.

The preceding specific embodiments are illustrative of the invention. Itis to be understood, however, that other expedients known to thoseskilled in the art may be employed without departing from the spirit ofthe invention or the scope of the appended claims.

TABLE castrated rat donor Intact rat receiver Body weights in gm.

Body weights in gm.

Daily doses Uterus, Ovaries, Uterus Groups 1117 Original Final mg.Original Final mg mg 0 74 91 a4. 54 68 B9 182. 00 189. 96 (mm animals o76 93 41. 22 74 106 157.154 185. 0s 33 SS g7 83 2; 9g 77 21.56 75.84 7723.52 100.15 mmthymdrel 10 7s s1 s2. 43 60 94 as. 75 155. 76 5 73 9644.84 71 94 143.30 150. 70 75 72 97 13a 66 70 as 29. as 115. 28 so 75 7am. 70 71 87 a4. 05 111. so Raeemie t7aethynyl-8a-H-Aestrenel713-ol-3-one 25 73 78 117. 91 70 B6 28. 08 86. 70 1o 74 82 97.65 73 a4 27. as 92. 82 a 76 89 10s. 74 83 49. 00 11s. 56

It can be ascertained from these data that with obvi We claim:

ously equal estrogenic activity (increase of the weight of the uterus ofthe castrated partner), 17aethynyl-8a-H- A -estrene-l7fi-ol-3-one is asactive as a dose of 10 as norethynodrel at a dose of 207 as hypophysialinhibitor. Racemic l7a-ethynyl-8a-H-A -estrene-l7fi-ol-3-one is,therefore, twice as active as norethynodre].

(2) Antifertilizing activity in the rat (A) Action on the implantationof fertilized ova: The test described by Pincus and Banik in Proc. Soc.Exp. Biol. Med. 1962, 111, 595, was employed.

Some rats were treated from the first day of gestation (verified by thefinding of spermatozoids in vaginal smears) until the third day withincreasing doses of levorotatory 17m-ethynyl-8e-HA-estrene-17,9-ol-3-one (in dioxane). On the 10th day the animals weresacrificed and the points of implantation were counted. The levorotatoryl7a-ethynyl-8a-H-A -estrene-l7fl-ol-3-one (in dioxane) and norethynodrelwere daily administered orally at a volume of 1 cc. per animal.

l. A method of curbing excessive hypophysial activity in warm-bloodedanimals which comprises administering to warm-blooded animals from about0.04 mg./kg. to about 6.0 mg./kg. per day, based on the body weight ofsaid warm-blooded animals, of a compound selected from the groupconsisting of the racemic and optically active forms ofl7a-ethynyl-8a-H-A -estrene-17fl-ol-3-one.

2. A method of suppressing ovulation in warm-blooded animals whichcomprises administering to warm-blooded animals from about 0.04 mg./kg.to about 6.0 mg./kg. per day, based on the body weight of saidwarm-blooded animals, of a compound selected from the group consistingof the racemic and optically active forms of 17methynyI-SwH-A-estrene-l75-ol-3-one.

3. A method of suppressing fertilization of the ova in warm-bloodedanimals which comprises administering to warm-blooded animals from about0.04 mg./kg. to about 10.0 mg./kg. per day, based on the body weight ofsaid warm-blooded animals, of a compound selected from the 10 OTHERREFERENCES group consisting of the Iacemie and optically acxivc formsJournal Amer. Chem. Soc. (1959), p. 3l20-3124 by of 17a-ethynyl-8a-H-AReferences Cited X Cdenc et UNITED STATES PATENTS 5 ELBERT L. ROBERTS,Primary Examiner 3,178,456 4/1965 Wettstein et a1. 260-6914 3,248,4054/1966 Fried eta! 260-397.4 60 73955 3974 CL Zak-239.55

3,270,007 8/1966 Alvareg

